DID - Feb. 12, 2008 Issue

Vol. 7 No. 29

Baxter Suspends Multidose Heparin Production After Allergic Reactions

Baxter and the FDA are investigating manufacturing facilities and processes for multidose Heparin after a spike in serious adverse events associated with it caused the company to suspend production of multidose vials of the drug.

Four people have died after receiving heparin, although the relationship to the drug is unclear, the FDA said in a Feb. 11 public health advisory. The suspension involves only multidose vials of the drug, which have been linked recently to such severe allergic reactions as unresponsiveness, throat swelling and rapidly falling blood pressure. Reactions to bolus doses from multiple single-dose vials also have been reported, the FDA said in a MedWatch report.

Roughly 350 adverse events have been reported since the end of last year, compared with fewer than 100 reports in 2007, the agency said. Approximately 40 percent of these reports appear to be serious adverse events.

Information in January of allergic-type reactions prompted Baxter to recall nine lots of multidose vials Jan. 17. However, the FDA has since learned of adverse events beyond the recalled lots.

The root cause of these reactions has not been determined, the FDA said. It is continuing to analyze adverse event reports and is testing samples of multidose heparin from Baxter’s facilities. Although the investigation is focused on manufacturing, the source of the allergic reactions could be something far along in the production chain, such as vials or rubber stoppers, according to John Jenkins, director of the Office of New Drugs.

“Very trace amounts of contaminants can cause these types of reactions when you give them in large doses intravenously,” he said.

While the investigation continues, vials in distribution will not be recalled, the agency said. The FDA is checking for similar concerns with products from APP Pharmaceuticals, the other approved manufacturer of multidose heparin, although it said it is not aware of any at this time.

The agency also is working to identify alternate sources of heparin in case Baxter’s manufacturing suspension continues. Baxter provides approximately half of the U.S. supply of heparin.

Heparin is commonly used before certain types of surgery and in kidney patients before they undergo dialysis. The reported adverse events occurred in patients given a high dose of heparin directly into the bloodstream over a short period of time. — April Astor

Black Box Warning Urged for Botox

Public Citizen is calling for a black box warning on Botox injections, saying the FDA’s early communication did not go far enough to warn physicians and patients about risks with the drug.

The group recently filed a petition with the FDA asking the agency to increase its warnings about Allergan’s Botox and Botox Cosmetic (botulinum toxin type A) and Solstice Neurosciences’ Myobloc (botulinum toxin type B).

Last week, the FDA said the drugs had been linked to serious adverse events, including respiratory failure and death after being used for a variety of conditions (DID, Feb. 11). The agency will announce its conclusions and recommendations once it completes a review of clinical trial safety data and postmarketing adverse event reports for the drugs.

“The FDA must do much more than send out a press release about its concerns,” Public Citizen Health Research Group Director Sidney Wolfe said. The agency should send warning letters to all physicians who administer Botox and Myobloc, as well as require the physicians to distribute medication guides to patients receiving injections, he added.

The agency must “immediately force” drug manufacturers to send out warning letters about the drugs’ risks to physicians, Public Citizen said. Regulatory agencies in the UK and Germany have sent “dear doctor letters” telling physicians to monitor patients receiving botulinum toxins.

In its review of the FDA’s data, Public Citizen found 180 serious adverse events, including 16 deaths, reported in the U.S. after use of the drugs between Nov. 1, 1997, and Dec. 31, 2006. Four children younger than 18 died, the group said.

The FDA does not know the cause of the adverse events but noted some of the most serious events occurred in children treated for limb spasticity associated with cerebral palsy, which is not an approved use.

Cipher Says No New Trial, Only New Analysis for Tramadol

Cipher Pharmaceuticals said the FDA has asked it to do additional statistical sensitivity analysis of existing clinical data on its atypical opioid pain reliever CIP-Tramadol ER.

The drug is Cipher’s extended-release formulation of tramadol. The additional data could “potentially satisfy the requirements for approval,” Cipher said.

In December 2007, Cipher appealed the FDA’s May 2007 approvable letter for the drug, in which the agency said an additional clinical trial would be needed. The company received a written response from the agency Feb. 1 that defended the approvable letter. In subsequent discussions with Cipher, the FDA told the company that a new analysis could be an alternative, apparently backing down from its request for a new clinical study.

Cipher said it is suspending its appeal of the approvable letter for now and expects to meet with the FDA in the near future to obtain further details on the proposed analysis. FDA spokeswoman Karen Mahoney said the agency cannot comment on clinical trials or approvable letters.

The FDA recently rejected in writing an appeal of an approvable letter for another formulation of tramadol produced by Canadian company Labopharm while suggesting that the firm do additional statistical analysis of existing data (DID, Jan. 25). — Martin Gidron

In the face of plummeting sales in 2007 for his company’s Type 2 diabetes treatment Avandia, GlaxoSmithKline’s (GSK) outgoing CEO, Jean-Pierre Garnier, is highlighting the need for pharmaceutical companies to become more proactive in handling emerging drug safety issues that result from highly publicized meta-analyses.

Sales of the Avandia (rosiglitazone maleate) franchise of products fell dramatically following publication of such an analysis in the New England Journal of Medicine (NEJM). It concluded Avandia increased the risks of cardiovascular adverse events. According to Garnier, press reports exaggerated the risks of the product, resulting in unwarranted patient demands to be taken off the medication (DID, Nov. 30, 2007).

Researchers readily can see trial results because most pharmaceutical companies, including GSK, post clinical trial databases on the internet. “It’s fairly easy to poke at those databases [and] combine data sets in different ways until you find some kind of a [drug safety] question,” Garnier said during the firm’s year-end earnings call. “That’s what the meta-analyses do. They don’t give any answers. They just raise a question.”

GSK recorded $266 million in U.S. sales for Avandia products during the fourth quarter, a decline of 55 percent compared with the same period the previous year. In 2007, the Avandia franchise had $1.56 billion in U.S. sales, down 29 percent from 2006.

“There are lots of lessons learned from what happened in ’07 for the pharmaceutical industry,” Garnier said. “You should do the meta-analysis, as we did with Avandia, but then you should absolutely demand that [the results] would be issued and put in context by the appropriate authorities. That didn’t happen in every country.”

The safety issues for Avandia came out in May 2007 with the NEJM study. Yet the FDA did not act until November 2007, according to Garnier, and major damage was done to the product franchise during the interim.

“There is no way for the scientist to be able to capture a question coming from a meta-analysis and have an instant answer. They need to look at the entire body of evidence. They need to look at all the long-term studies, as did the FDA with Avandia,” Garnier said.

In Europe, the decline in Avandia prescriptions was not as significant, Garnier explained. Although European sales were negatively affected, regulators and payers saw it for what it was, a relatively minor safety signal, Garnier indicated.

The problem of highly publicized yet unconfirmed safety issues brought to the forefront by meta-analyses in the media will not disappear for the pharmaceutical industry. The fundamental drivers are in place already, Garnier said.

In addition to patient demands that their medication be switched, these safety concerns can affect the payer environment. Insurance companies do not always wait for the FDA to act as well, Garnier said.

“You could quickly lose formulary position for reasons which are not solid,” Garnier said. “We have seen payers jump in and take a stand while the dust has clearly not settled and before the body of scientific evidence has been really reviewed in an appropriate way. And that is also something that needs to be managed very carefully,” Garnier said. — Christopher Hollis

AstraZeneca Seeks Additional Seroquel Approvals in EU

AstraZeneca has filed an application in the European Union (EU) for Seroquel XR to treat bipolar manic episodes and bipolar depressive episodes.

The company filed supplemental new drug applications for the same indications with the FDA earlier this year. Last year, the FDA approved Seroquel XR (quetiapine fumarate) to treat schizophrenia, giving the extended-release formulation of the drug patent protection until 2017 (DID, May 21, 2007).

In addition, the company filed an application in the EU for immediate-release Seroquel to treat bipolar depression. The FDA approved Seroquel for that indication last year.

Seroquel’s application includes data from the EMBOLDEN clinical trials, which studied more than 1,500 patients. The complete data will be published in the upcoming months, the company said.

In the U.S., AstraZeneca is in legal battles over Seroquel’s patent protection against generic drugmakers Teva Pharmaceuticals and Sandoz (DID, Feb. 11). The FDA recently decided that, because Seroquel 150-mg tablets have not been withdrawn from the market for safety or efficacy reasons, the agency can accept and approve applications for generic versions of the drug (DID, Jan. 25). AstraZeneca markets 25-, 50-, 100-, 200-, 300- and 400-mg Seroquel tablets in the U.S.

Worldwide sales of Seroquel exceeded $4 billion in 2007, according to the company. — Emily Ethridge

GSK-Adolor Drug Faces Another Hurdle

The FDA has extended the action date on the new drug application for GlaxoSmithKline (GSK) and Adolor’s opioid receptor antagonist Entereg to treat postoperative ileus (POI).

The original Entereg (alvimopan) action date was Feb. 10. However, the agency now will make its decision May 10. Michael Dougherty, Adolor’s president and CEO, said the company also submitted a revised risk-management program for the drug to ensure its appropriate use in patients for whom it has demonstrated a favorable risk-benefit profile.

POI is a condition that occurs after gastrointestinal surgery, causing nausea, vomiting, abdominal pain and intolerance to food and liquids. The condition complicates recovery leading to longer hospital stays.

The announcement of the delay comes less than a month after the FDA’s Gastrointestinal Drugs Advisory Committee voted 9–6 that the overall benefits of Entereg outweigh its potential risks in the treatment of POI. The split vote centered on the safety of Entereg, not its efficacy (DID, Jan. 24).

Safety issues have plagued development of the product. In 2006, the agency requested a risk-management plan and further safety data from an ongoing trial known as Study 104 (DID, Nov. 7, 2006). Last spring, the firms suspended various clinical studies, including a study in patients with opioid-induced bowel problems and a study involving cancer patients, due to a potential safety signal for tumors (DID, April 11, 2007). — Elizabeth Jones